JPS6233129A - Rectal administration medicine containing beta-lactam antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention utilizes a β-lactam antibiotic as an active ingredient, an excipient, and an enhancer (CNL+ANCR) that promotes the absorption of the antibiotic into the rectum, thus reducing the amount of antibiotic drug in the blood. The present invention relates to rectal dosage forms, especially suppositories, containing substances that provide a physiologically effective amount.

It is known to use rectal dosage forms, such as suppositories, to release orally inactive beta-lactam antibiotics.

Moreover, eel suppositories are usually made from antibiotics, long-chain (C12 ~ Tsuru (
It consists of excipients of the type Witepsol (for example Witerbusolt is) and substances that promote the absorption of antibiotics into the rectum. In the past, probenecid and
Fatty acids with chain lengths of 8 to CI4 have been used in suppository forms to enhance absorption of antibiotics. Furthermore, the use of mixtures of C2-Cl2M fatty acid glycerides as enhancers has also been described.

According to the present invention, the enhancer used to promote rectal absorption of β-lactam antibiotics is he/deoheshifric acid (
chcnodeoxycholic acid) or its sodium salt.

According to the invention, the excipients used for formulating the rectal dosage forms are mixtures of higher, especially glycerides of CI2 to C+s fatty acids, preferably of fatty acids having an even number of carbon atoms.

Suitable β-lactam antibiotics include those known in the art having a β-lactam ring as the central ring system. As an example, a compound R having the following general formula, R101<2, where R1 is hydrogen or optionally substituted lower alkyl, %R2 is SO, -M+, and M+ is a proton or a pharmaceutical compound, ? 'F-containing cation, 1
(, is an acylamine/or lower hydroxyalkyl group; or R1 and R2 are -41 together with the β-lactam (azene) ring to which it is attached to form a compound of the general formula, where X is -5-1-O-1-S
O-1-8O2-t, Ta1i-CH2-woarashi,
and Y represents the following group, where the carbon atom bearing the -COOE group is bonded to the nitrogen atom of the β-lactam ring, and Z is hydrogen, halogen, lower alkoxy or -CH2-T group. , T is hydrogen, lower alkanoyloxy, bilinonium, carboxamide bilinonium or ami/pyridinium group, carbamoyloxy, and, cyano, hydroxy, optionally substituted -3-phenyl group or -8- 1+ct1L, where l'+ e
t1. 5- or 6- optionally substituted with
and E represents hydrogen or a pharmaceutically acceptable ester-forming group or salt-forming cation; and hydrates of these compounds.

Particularly preferred β-lactam antibiotics are cerLriaxone, cefamandole (c
ef amandole) and cefazolin (cc
cephalosporins, including fazol in, mono-β-lactams, including carmonam, and penicillins, including piperacillin and mezlocillin.

In one particularly preferred embodiment of the invention, Ce7 triaxone is used as the β-lactam antibiotic.

A preferred vehicle useful in formulating rectal dosage forms is a glyceride mixture consisting of triglyceride weights of L-saturated C1-C, Wi fatty acids, preferably fatty acids having an even number of carbon atoms.

The most preferred glyceride mixture is Huitepsol (W
i Lcpsol ) type, in particular Uiterpsol H-15. Examples of such Huitepsol are as follows: Rectal dosage forms according to the invention contain active substances such as cefazone, cefamandole, mezlocillin, cefazolin, piperacillin or carmonam, preferably about 25
8 to about 2000mg, especially about 50mg to about 500+o
Contains vinyl.

The active substance/excipient ratio in the rectal dosage form according to the invention is conveniently between about 3:1 and about 1:20, preferably between about 1:1 and about 1:3; and most preferably about 1:2. The active substance/enhancer ratio is conveniently between about 1=2 and about 24:1, preferably about 2
:1 to about 8:1, most preferably about 4:1.

Based on the beta-lactam antibiotic, the rectal dosage form preferably contains 1 part beta-lactam antibiotic, about 1 to 3 parts excipient,
and 0.125 to 0.5 parts of enhancer, especially β-
1 part lactam antibiotic, about 2 parts excipient and 0.0 parts enhancer.
Contains 25 parts. Typical Fri enteral dosage form - containing 500 μg of lactam antibiotic, 1275 μg of excipient and 125 μg of enhancer.

Pharmaceutical compositions for rectal dosing according to the present invention are generally formulated to be fluid by dispersing the pharmacologically active substance, henodeoxycholic acid or its sodium salt, and excipients and other ingredients in a liquid oil carrier. (e.g., suspensions, ointments, gels, creams, etc.) and the preparations are placed in soft rectal gelatin capsules or syringes.
Rectal suppositories or i1! ! Used in preparations, for example as enemas.

The rectal dosage forms according to the invention can also contain auxiliary agents known per se in order to obtain the desired consistency. Additionally, water-soluble carriers such as polyethylene glycol, polypropylene glyconopeglycerogelatin, methylcellulose or carboxymethylcellulose can be included. Also lubricants, such as polyoxyethylene rubitan fatty acid esters, polyoxyethylene sorbitol fatty acid esters, polyoxyethylene fatty acid esters, glycerin fatty acid esters, such as mixtures of fatty acids, mono- or triglycerides, and higher alcohol esters of polyoxyethylene. Non-ionic wetting agents such as or anionic wetting agents such as esters of lower furkylsulfonic acids or cationic surfactants are also contemplated. In addition, rectal dosage forms can contain suitable emulsifying and dispersing agents, agents for adjusting viscosity, and coloring substances.

These dosage forms are prepared in accordance with the invention by melting the excipients by heating (e.g., at a temperature above 45°C, preferably between about 45°C and 60°C) and adding the enhancer and the active substance to the resulting melt. and, if desired, homogeneously disperse conventional pharmaceutical adjuvants for direct HJjI formulations and formulate the resulting dispersion into rectal dosage forms such as suppositories, rectal capsules or rectal delivery systems. It can be created by

The high bioavailability level of the active substance when incorporated into a rectal dosage form according to the invention can be demonstrated by the method detailed below using suppositories consisting of the dimensional component for Se7triacman: Triacundisodium salt trihydrate 600B 60 (hg
[Equivalent to Se7 Triacman 502.2+ag (83.7%) 1 Uitepsol H-152675111111275 sog
Henodeoxycholic acid sodium salt "Kakitari" μKi L340
The bioavailability of Se7triacman was extensively tested using intravenous administration into a baboon model as a standard: For intravenous dosing, baboons were administered ketamine hydrochloride (5 to
The animals were sedated by intramuscular injection of 10 mBl kg). Next, after drawing a zero-time blood sample, Se7triacman solution 11 was injected into the upper vena cava in 9 parts of the leg.

For rectal dosing, baboons were tied and immobilized for 24 hours before drug administration. After drawing a blood sample at zero time, the suppository was pushed into the rectum using a rasp rod. The rectal opening was taped for approximately 20 minutes to prevent expulsion or leakage of the suppository.

Plasma concentrations of Se7triacman were assayed as follows: Blood samples were collected at time zero (before drug administration) and at 5.30.60, 120, 240.360.480.6 after drug administration.
00.720 and 1440 minutes. Blood was drawn from a vein in the large UIS region using a heparinized syringe. Blood 11 was placed in a heparinized centrifuge tube and centrifuged for 30 seconds.

Plasma was removed and frozen at -20°C until analyzed for serum concentration.

Plasma samples were deproteinized with acetonitrile and antibiotic levels were determined on agar plates by E. coli (E.
-coli) 1346 was used as the microorganism and tested by microbiological assay method. Plasma concentrations were then calculated based on antibiotic levels and plotted as a function of time for both rectal and venous data. Song 1 (AUG
) and calculate the corrected percentage of Bio7 availability from the following formula: The results obtained for the above suppositories are as follows: : Average peak plasma level (APPL) Cmax=75°9
±19.6 parts g/wrl; average bioavailability-(AB)=68.5±6.6% and according to the above method and compound carmona, piperacillin;
Using similar formulations for cefamandole, cefazolin and mezlocillin, the following results were obtained: Carmonam 5. '6 47.0 Piperacillin 1.2 27.0 Cefamandole 22 100.0 Cefazoline 4255 Mezlocillin 343 Low Cm of carmonum, mezlocillin and piperacillin
It should be noted that ax levels are maintained over long periods of time, which contributes to the low level but increased bioavailability of C+nax.

Claims (1)

[Scope of Claims] 1. A therapeutically effective amount of a β-lactam antibiotic, an enhancer for promoting rectal absorption of the β-lactam antibiotic, and an excipient consisting of a mixture of higher fatty acid glycerides; is henodeoxycholic acid or its sodium salt. 2. The rectal administration preparation according to claim 1, wherein the β-lactam antibiotic is ceftriaxone, piperacillin, carmonam, cefamandole, cefazolin or mezlocillin. 3. The rectal administration preparation according to claim 1 or 2, wherein the β-lactam antibiotic is ceftriaxone. 4. Rectal administration preparation according to any one of claims 1 to 3, wherein the excipient is a glyceride mixture of the type Huitepsol. 5. The rectal administration preparation according to claim 4, wherein the Witepsol is Witepsol H-15. 6. The rectal formulation of any of claims 1 to 5, wherein the ratio of β-lactam antibiotic to excipient is about 3:1 to 1:20. 7. The rectal formulation of claim 6, wherein the ratio of β-lactam antibiotic to excipient is about 1:1 to about 1:3. 8. The rectal formulation of claim 7, wherein the ratio of β-lactam antibiotic to excipient is about 1:2. 9. The rectal preparation according to any one of claims 1 to 8, wherein the ratio of β-lactam antibiotic to henodeoxycholic acid or its sodium salt is from about 1:2 to about 24:1. . 10. The rectal formulation of claim 9, wherein the ratio of β-lactam antibiotic to henodeoxycholic acid or its sodium salt is from about 2:1 to about 8:1. 11. The rectal preparation according to claim 10, wherein the ratio of β-lactam antibiotic to henodeoxycholic acid or its sodium salt is about 4:1. 12. According to any of claims 7 and 10, the ratio of β-lactam antibiotic to excipient to enhancer is about 1:1 to 3:0.125 to 0.5. Rectal formulation. 13. Claims 8 and 1 wherein the ratio of β-lactam antibiotic to excipient to enhancer is about 1:2:0.25.
Rectal administration formulation according to any one of Item 1. 14. β-lactam antibiotic approx. 500 mg, excipient approx. 1
Rectal administration formulation according to any one of claims 1 to 5, containing 275 mg and 125 mg of enhancer. 15. The rectal administration preparation according to any one of claims 1 to 14, which is a suppository, rectal capsule, syringe, or tube. 16. The rectal administration preparation according to claim 15, which is a suppository. 17. In producing a rectal preparation containing a β-lactam antibiotic as an active substance, henodeoxycholic acid or its sodium salt is added as described in claim 1, 4 or 5. Method of use in combination with excipients. 18. In producing the rectal administration preparation according to any one of claims 1 to 16, henodeoxycholic acid or its sodium salt is added to claim 1,
A method for use in combination with an excipient according to item 4 or 5. 19. A rectal formulation containing a therapeutically effective amount of a β-lactam antibiotic, an enhancer to promote rectal absorption of the β-lactam antibiotic, and an excipient consisting of a mixture of higher fatty acid glycerides is prepared by known methods. A method characterized in that henodeoxylycolic acid or its sodium salt is used as an enhancer. 20. Melt the excipients by heating and homogeneously disperse in the resulting melt the enhancer and the β-lactam antibiotic and, if desired, the customary pharmaceutical auxiliaries for rectal formulations. and formulating the resulting dispersion into a rectal administration formulation. 21. The method according to claim 20, wherein the resulting dispersion is formulated into suppositories. 22. The β-lactam antibiotic, excipients and enhancers, and, if desired, conventional pharmaceutical adjuvants for rectal formulations are dispersed in a liquid oil carrier to form a flowable formulation; 20. The method of claim 19, comprising filling the formulation into a rectal capsule, syringe or tube.